Several lines of evidence suggest that endogenous opioid peptides, enkephalin and dynorphin play important roles in modulating the excitability of the hippocampus. However, the information regarding the regulation of these two opioid peptides has been lacking. The purpose of this project was to examine the molecular mechanisms of the expression of enkephalin and dynorphin in the hippocampus by excitatory amino acids or hormones, such as glucocorticoids. Previous results from our laboratory indicate that stimulation of perforant pathway, which innervate dentate granule cells, elicits differential effects on the hippocampal levels of opioid peptides: increase in enkephalin, but decrease in dynorphin. To study the neurotransmitter(s) which regulate the metabolism of dynorphin in the dentate granule cells, two sets of experiments were performed. First, to examine the possibility that glutamate, which releases from the perforant path following stimulation, may be responsible for the down regulation of dynorphin, a glutamate receptor blocker, gamma-D-glutamylglycine (gamma-DGG) was employed. Daily DGG pretreatment significantly inhibited stimulation-induced decrease in dynorphin content in both dorsal and ventral hippocampus. This result was further supported by in situ hybridization which measures the abundance of pro-dynorphin mRNA levels. These data strongly suggest that glutamate as the endogenous neurotransmitter at perforant synapses mediates stimulation-induced synaptic excitation and regulates the release and biosynthesis of dynorphin in dentate granule cells.Second, we found elevated hippocampal level and its mRNA abundance in aged rats (24-28 months) compared with 6 month old rats. The increase in the expression of dynorphin was correlated with the decreased release of glutamate in the hippocampus. Taken together, these data clearly indicate that glutamate plays a major role in regulating the expression of dynorphin.